pH-Responsive Dipeptide-Based Dynamic Covalent Chemistry

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Interface-Rich Materials and Assemblies

pH-Responsive Dipeptide-Based Dynamic Covalent Systems Where Products and Self-Assemblies Depend on Structural Isomeric Aromatic Dialdehydes Yajie Wang, Pengyao Xing, Wei An, Mingfang Ma, Minmin Yang, Tianxiang Luan, Ruipeng Tang, Bo Wang, and Aiyou Hao Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b04397 • Publication Date (Web): 24 Oct 2018 Downloaded from http://pubs.acs.org on October 24, 2018

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pH-Responsive Dipeptide-Based Dynamic Covalent Chemistry Systems Which Products and Self-Assemblies Depend on Structure Isomeric Aromatic Dialdehydes Yajie Wang, Yang,

†

†

Pengyao Xing,

Tianxiang Luan,

†

‡

Wei An,

†

Ruipeng Tang,

Mingfang Ma, †

Bo Wang

†

†

Minmin

and Aiyou

Hao*† †Key

Laboratory

of

Colloid

and

Interface

Chemistry

of

Ministry of Education and School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China. ‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore.

KEYWORDS: self-assembly, dynamic chemical bonds, reversible pH-responsiveness,

gel,

vesicle,

organic

structure isomerisms.

ABSTRACT

ACS Paragon Plus Environment

nano

particles,

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Facile control over preparation of organic building blocks and

self-assembled

aggregations

to

construct

desired

materials remains challenges. This paper reports selective dynamic covalent bond formation and the corresponding selfassembly

behaviors

by

using

a

dipeptide,

glycylglycine

(GlyGly), reacting with isomeric aromatic dialdehydes orthophthalaldehyde (OPA), para-phthalaldehyde (PPA) and metaphthalaldehyde (MPA), to demonstrate diversified aggregation forms caused by structure topology variations. Under alkaline condition,

aldehyde

groups

of

phthalaldehydes

can

be

connected with amino groups of GlyGly by imine bonds as the dynamic chemical bonds. Owing to the fact that formation and dissociation of the imine bonds were reversibly pH-responsive, the reactions and aggregates assembled by their products were also reversibly controlled by changing pH. Three products, including

two-armed

product

(OPGG,

in

which

two

GlyGly

molecules were connected with a OPA molecule), single-armed product (PPG, in which only one GlyGly molecule was connected with a PPA molecule), a mixtrue product (MPGG and MPG) as well as their different self-assembly behaviors were obtained from OPA/GlyGly, PPA/GlyGly, MPA/GlyGly systems respectively at the same condition, pH 8.6 in 90% methanol aqueous solution. While

for

OPA/GlyGly

system,

another

different

type

of

product with benzopyrrole structure (OPG) was obtained by


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nucleophilic substitution via mixing OPA and GlyGly in water, which generated organic nanoparticles. Based on the results above, we conjectured the differences of dynamic covalent bond

formation

and

supramolecular

assembly

clearly

were

influenced by the structure topologies of phthalaldehydes (OPA, PPA and MPA). The experimental phenomenon verified the hypothesis as well, which may guide us to realize facile construction of selective reaction products and intelligent reversibly responsive materials with diverse morphologies and functions.

Introduction Facile

designing

of

diverse

intelligent

materials

with

reversible stimuli-responsiveness has been persisted over many decades.

1-3

Selective modulation of organic building

blocks and their self-assembled aggregations are promising approaches in materials design.

4

Small organic molecules are

usually chosen to construct functional building blocks for their interactions controlled easily by adopting reasonable structures.

5-7

Dynamic chemical bonds are protruding for its

advantages and have been extensively explored in the field of supramolecular science,

8-12

as they are similar to noncovalent

interactions due to the dynamic nature. Compared with the


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instability of noncovalent bonds, dynamic chemical bonds are kind of relatively stable covalent bonds with dynamic feature, which are desirable for constructing structural controllable materials and have already been used to control the formation of functional building blocks. nature

of

dynamic

chemical

13-27

Owing to the reversible

bonds,

the

structures

and

morphologies of the aggregates assembled from the building blocks

are

modulation

easier is

to

be

important

modulated in

the

reversibly. design

of

28,

29

The

intelligent

materials which reflects the structure-property relationship. 30

Among the various dynamic chemical bonds, benzoic imine bonds are especially widely adopted because its dynamic equilibrium is readily achievable and extensively existed. fabricated

in

alkaline

environment

and

31

It can be

hydrolyzed

under

acidic condition. The unique nature of this dynamic chemical bond is confirmed reversible and has been widely employed to fabricate reversibly pH-responsive assemblies. van Esch et. al.

18, 33, 34

32

For example,

utilized the dynamic benzoic imine

bonds to fabricate different types of organic small molecular building

blocks

micelles

and

which

gels

with

can

self-assemble

controllable

into

vesicles,

characteristics

by

forming and rupturing of dynamic imine bonds. Reversible


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morphology transformations such as vesicles to fibers have also been developed relaying on dynamic benzoic imine bonds. By controlling pH, recently we have successfully fabricated facilely

stimuli-responsive

nanofiber dynamic

to

supramolecular

covalent

aldehydes

transformation

and

gel 35

chemistry.

aliphatic

via

In

amines

vesicle

ω-amino

these

were

of

acid-based

cases,

chosen

to

aromatic

to

construct

assembled building blocks via dynamic imine bonds, while the self-assembled systems were usually single and only one type of geometric topology was investigated. Structure

isomerisms

covalent

bond

covalent

bonds,

have

chemistry.

important In

different

the

effects

reaction

structure

on

dynamic

with

dynamic

isomerisms

of

the

reactants have different link site of dynamic covalent bonds, which determining diverse resultants with dynamic covalent bonds. Though it is a promising approach to construct various intelligent

responsive

materials,

there

are

barely

any

protocols developed for well understanding multiple dynamic covalent

bond

isomerisms. influence

chemistry

In of

this three

phthalaldehydes,

systems

paper,

we

different

ortho,

para

with mainly

diverse

investigated

structure

and

isomerisms

meta-positon


structure

and

the of

their

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products, two/one-armed dynamic bonds building blocks, on self-assemble behaviors of the systems. Herein, we report three distinguishing reversible assembly systems, OPA/GlyGly PPA/GlyGly and MPA/GlyGly and their selfassemblies, fabricated from different structure isomerisms of building blocks, based on benzoic imine bonds. (Scheme 1) For OPA/GlyGly system, the two aldehyde groups of OPA molecules were both able to connect with the amino groups of GlyGly molecules via imine bonds to form two-armed product (OPGG), which can further self-assemble into a rufous-colored gel via H-bonding and π-π stacking interactions under pH 8.6 in 90% methanol aqueous solution. The gel showed reversible pHresponsiveness PPA/GlyGly

due

system,

to

the

only

dynamic

imine

single-armed

bonds.

product

But

for

(PPG)

was

detected at the same reaction conditions compared with the OPA/GlyGly system, which signified only one aldehyde group in each PPA molecule reacted with GlyGly. Moreover, unlike the OPA/GlyGly system, the product PPG was found assembling into vesicles at the reaction condition (50 mM), and the vesicles were also reversibly controllable by changing pH. While for MPA/GlyGly system, single-armed product (MPG) and two-armed product (MPGG) were both appeared, and no aggregates was observed. In addition, during investigating the reaction of


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OPA

and

GlyGly,

another

type

of

reaction

was

found

unexpectedly. The product with a benzopyrrole structure was obtained by nucleophilic substitution via mixing OPA and GlyGly in water, as well as its self-assembled aggregates, organic nanoparticles.

Scheme 1. GlyGly with different structure isomerisms of phthalaldehydes, OPA PPA and MPA, fabricating distinguishing reversible building blocks and self-assembly behaviors based on benzoic imine bonds.

Experimental Section Materials o-Phthalaldehyde phthalaldehyde

(OPA), (MPA)

and

p-phthalaldehyde glycylglycine


(PPA), (GlyGly)

mwere

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purchased from Aladdin Chemical Reagent Co. Ltd, Shanghai, China. All the other reagents are of analytical reagent (AR) grade and were purchased from country medicine reagent Co. Ltd. (Shanghai, China). All chemicals were used as received without further purifications. Preparation of samples GlyGly (1.32 g, 10 mmol) and OPA (0.67 g, 5 mmol) were mixed together in 100 ml 90% methanol aqueous solution with a molar ratio of 2:1, and proper amounts of KOH were added to tune the pH value to 8.6. The mixed solution was kept stirring at 40℃ for 2 hours, a clear rufous solution was obtained. After evaporated

and

washed,

rufous

powder

was

obtained.

Same

method was adopted for PPA/GlyGly and MPA/GlyGly systems. The reaction route is shown in Scheme 1.


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Scheme 2. Reaction route of GlyGly with OPA PPA and MPA. Characterization Proton

nuclear

magnetic

resonance

(1H

NMR)

spectra

of

OPA/GlyGly PPA/GlyGly and MPA/GlyGly systems were measured on a Bruker AM-400 spectrometer at room temperature with DMSOd6 or D2O as the solvent and TMS as the reference. Electrospray ionization mass (EMI-MS) spectrum was performed on API 4000 MS equipment. The samples were dried in vacuum for 12 h until become dried powders at room temperature. The dried samples of product of OPA/GlyGly PPA/GlyGly and MPA/GlyGly systems,


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solid samples of GlyGly OPA PPA and MPA were measured by an Avatar 370 Fourier-transform infrared (FT-IR) Spectrometer. KBr was used as the sample disks. The samples for transmission electron microscope (TEM) were measured on a JEM-100CX II electron

microscope

(100

kV).

Field-emission

scanning

electronic microscopy (SEM, Hitachi S-4800) was used to study the microstructures of the samples. The rheology of the gels was directly tested by a Thermo Scientific HAAKE RheoStress 6000. Absorption spectra were recorded on a Shimadzu UV-3600 spectrophotometer.

Small-angle

X-ray

scattering

(SAXS)

measurements were carried out using an in-house set-up with rotating anode X-ray generator (Rigaku RU 300, 12 kW) equipped with two laterally graded multilayer optics in a side-by-side arrangement, giving a highly focused parallel beam of monochromatic Cu Ka radiation. Dynamic light scattering (DLS) measurements were carried out with a Wyatt QELS Technology Dawn Heleos instrument set at constant room temperature by using a 12-angle replaced detector in a scintillation vial and a 50 mW solid state laser (k = 658.0nm). All solutions for DLS were filtered through 0.80 μm filters before detection.

Results and discussion


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OPA/GlyGly system Reaction of OPA and GlyGly Under alkaline condition, the amine groups in GlyGly can be connected with the aldehyde groups in OPA by benzoic imine bonds. The molar ratio GlyGly:OPA is 2:1 to ensure that there were

molar

equivalent

amine

and

aldehyde

groups.

36

The

chemical structure of reaction product was confirmed by

1H

NMR spectroscopy under pH 8.6. As shown in Figure 1a, the signals

of

the

aldehyde

groups

at

10.5

ppm

(1)

in

OPA

disappeared. Because the molar ratio between amine groups and aldehyde is 1:1, the absence of the aldehyde proton signals indicates that nearly all the aldehyde groups had been reacted and converted.

29

EMI-MS spectrometry can also verify that

both aldehyde groups in OPA molecules had reacted with GlyGly and the two-armed product existed. (Figure S1) Two new signals appeared at 8.8 and 8.4 ppm (2, 3) in the product (OPGG), corresponding to the protons on the imine bonds. (Figure 1a) Further evidence of the formation of benzoic imine bonds is provided by FTIR. As shown in Figure S2, the characteristic IR band of the imine at 1665 cm-1 is clearly visible in the spectrum of the OPGG. Self-assembly behaviors


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The self-assembled behaviors of OPGG were investigated in detail. The 90% methanol solution of OPGG (3.8% wt) was found transforming into a fine self-supporting gel under ultrasound (40 kHz, 20min). As a stimulus, ultrasound can improve or trigger some self-assemblies, such as vesicles formation and gelation.

37-39

It has been reported that some small gelators

bearing H-bonding and π-π stacking sites readily form threedimensional networks after ultrasonication

40-42,

which can be

explained by accelerated nucleation and growth of fibers.

43

The morphologies of OPGG gel were studied by TEM and SEM. (Figure

1c-e)

Thin

layers

with

thickness

in

dozens

of

nanometers stacked together to construct a strong threedimensional networks that can trap solvents by capillary force,

immobilizing

solvent

molecules

from

flowing

macroscopically, leading to the formation of the gel. Highly stacked nanosheets could facilitate the formation of stable

supramolecular

organogels,

which

were

further

investigated by rheological studies. As shown in Figure 1b, the gel shows a linear viscoelastic region where the elastic modulus

G’

(solid-like

behavior)

is

higher

than

viscous

modulus G’’ (liquid-like behavior) over a wide applied stress region from 10 Pa to yield stress points, after which the gels collapse into a liquid state, exhibiting non-Newtonian


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fluid characteristics.

44

In the linear viscoelastic region,

solid character of the gel can be revealed.

1H

Figure 1. (a)

NMR spectra of OPA GlyGly and OPGG. (b)

Dynamic oscillatory stress sweep of the OPGG gel. (c)TEM and (e, f) SEM images of OPGG gel at room temperature, inset: digital images of OPGG gel. Mechanism research Noncovalent forces account for the formation of OPGG gel. FTIR and UV-vis spectra were employed to probe the H-bonding information and π-π stacking. As shown in Figure 2a, peaks of ν

N-H

= 3489 cm-1 and ν

O-H

= 3350 cm-1 in OPGG shift to 3431

cm-1 and 3334 cm-1 in xerogel, as well as the peak of ν 1665 cm-1, ν

C=O

cm-1,

cm-1

1595

= 1613 cm-1 and δ and

1520

N-H

cm-1,

C=N

=

= 1532 cm-1 shift to 1653 respectively.


The

lower

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Page 14 of 45

wavelength shift indicates that intermolecular hydrogen bonds are formed in the OPGG gel. N-H

and ν

O-H

45, 46

Furthermore, the peaks of ν

in OPGG gel becomes broader and stronger than

those in OPGG powders, which can also imply the formation of H-bonding in OPGG gel

47.

Figure 2b displays the UV-vis spectra

comparison of OPGG in DMSO and OPGG gel. OPGG molecules in DMSO

should

be

in

a

state

of

single

molecule

for

good

solubility. However, OPGG molecules in gel should be another state. The main absorption peak of OPGG in DMSO is 241 nm, which exhibits an obvious blueshift to 230 nm in OPGG gel, indicating the formation of H-type π-π stacking molecular model.

47, 48

Hence, H-bonding and π-π stacking may be the

driving forces for construction of the OPGG gel. To further explore the microstructures of molecular packing, we

employed

SAXS

which

were

often

structures of soft materials.

49, 50

best

cylinder

to

the

flexible

used

to identify

the

The scattering data fitted model,

signifying

metastructures or fabric structures existed in OPGG gel. (Figure 2c) The obvious peak was obtained with the d spacing of 1.73 nm, which is longer than the length of an OPGG molecule (ca. 1.34 nm, obtained from optimized molecular model based on Material Studio 5.5) but shorter than two. Considering

the

H-bonding

(O-H···N

and


N-H···O)

and

π-π

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stacking interaction (between benzene ring) of the OPGG gel, the d spacing is consistent with the overlapping molecules, and thus confirms the bilayer structures. structure

(Figure

2d)

is

in

good

43,

agreement

51

Lamellar with

the

assumptions regarding gel shrinkage and alignment/bundling of nanosheets induced by H-bonds and π-π stacking.

Figure 2. (a) FTIR spectra of OPGG and the xerogel. (b) UVvis spectra comparison of OPGG in DMSO and OPGG gel. (c) SAXS pattern and (d) molecular packing model of OPGG gel. pH-responsiveness.


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The OPGG gel was found pH-responsive. As shown in Figure 3a, when moderate amount of hydrochloric acid was added and the pH decreased from 8.6 to 6.4, the OPGG gel (Gel I) was dilapidated and precipitates appeared immediately. But, when equivalent potassium hydroxide was added, with the recovery of pH from 6.4 to 8.6, the OPGG gel (Gel II) was regenerated again.

Moreover,

the

new

OPGG

gel

can

be

destroyed

by

hydrochloric acid as well. This reversible process can be repeated several times. The morphology of the precipitates (Figure b, c) and Gel II (Figure f, g) was investigated by TEM and SEM, as well as the intermediate microstructure at pH 7.8 (Figure 3d, e). Comparing the morphology of Gel I (Figure 1c-e), when the pH was changed down from 8.6 to 6.4, the nanosheets in Gel I cracked into fragments which caused the collapsion of Gel I. Accompanied with the recovery of pH, dendritic fibers appeared (Figure 3d,e) and then entangled with

each

networks,

other

to

construct

immobilizing

a

solvent

strong

three-dimensional

molecules

from

macroscopically, leading to the formation of Gel II.


flowing

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Figure 3. (a) Digital image of pH-responsiveness of OPGG gel. TEM and SEM images of collapsed OPGG gel at pH 6.4(b, c), 7.8 (d, e) and Gel II at pH 8.6(f, g).


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Rheological properties of the regenerated gel (Gel II) were also explored. (Figure 4a) Compared with the Gel I, Gel II had good reversibility and almost repeated the mechanical properties of Gel I. It showed a linear viscoelastic region over a wide applied stress region, which implied that the Gel II had excellent strength as well. Nevertheless, the elastic modulus G’ and viscous modulus G’’ in Gel II were slightly lower than those in Gel I, which means the viscoelasticity of the

regenerated

gel

reduced

a

little

bit.

The

pH-

responsiveness of OPGG gel was entirely reversible, revealed by regeneration of the OPGG gel and G’, G’’ value when the pH of the system was changed back to the alkaline state and vice versa. The

pH-reversible

processes

of

OPGG

gel

incarnate

the

structure-property relationship. The benzoic imine bonds in OPGG molecules are a kind of dynamic chemical bond which is controllably formed by changing external environment, such as pH.

31

The

pH-reversible

process

of

OPGG

gel

should

be

attributed to the pH-responsive benzoic imine bonds, which can form under alkaline condition and can be hydrolyzed by changing

down

reversible.

As

the

pH.

shown

in

The

transformation

Figure

4b,

the

is

confirmed

reversible

responsiveness of benzoic imine bonds is probed by


1H

pHNMR.

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When the pH of OPA/GlyGly system is changed to 6.4, the chemical shifts at 8.8 and 8.4 ppm (2, 3) corresponding to the

benzoic

imine

bonds

disappear,

accompanied

by

the

enhancement of the signals at 11.4 ppm (1), which correspond to the aldehyde protons. When the pH is changed back to 8.6, the imine signals recover and aldehyde signals (2’, 3’) disappear again. All the evidence above confirms that the formation and decomposition of imine bonds are reversible controlled

by

pH

and

leading

to

the

pH

reversible

responsiveness of OPGG gel.

Figure 4. (a) Dynamic oscillatory stress sweep of Gel I and Gel II. G’ and G’’ value is pH reversible, going from pH 8.6 (cycles 0, 1, 2, 3, 4) to 6.4 (cycles 0.5, 1.5, 2.5, and 3.5). (b)

1H

NMR spectra of OPGG gel at different pH

values: 8.6, 6.4 and again 8.6.


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PPA/GlyGly system Reaction of PPA and GlyGly PPA was applied to react with GlyGly to investigate the effect of structure isomerisms on the reaction and self-assembly. The reaction and product properties were studied compared with the OPA/GlyGly system. Like the reaction of OPA and GlyGly, the amine groups in GlyGly can also combine with the aldehyde groups in PPA by benzoic imine bonds in alkaline condition. The molar ratio of GlyGly and PPA was 2:1 too, to ensure equimolar amine and aldehyde groups. Unexpectedly, unlike the reaction of GlyGly and OPA, in which the two aldehyde groups of OPA molecule were both connected with the amino groups of GlyGly molecule, only one aldehyde group in the PPA molecule coupled to the GlyGly at the same reaction condition. To confirm the chemical structure of the product of the reaction,

1H

NMR spectroscopy was performed on the

PPA/GlyGly system. As shown in Figure 5a, compared with the spectra of PPA, the peaks of aldehyde groups at 10.0 ppm (1’) retain and a new peak at 8.5 ppm (2) appears in the reaction product (PPG), corresponding to the protons on the imine bonds. The integral area ratio between the peak of aldehyde groups and imine bonds is about 1:1. Besides, according to the EMI-MS spectrometry (Figure S3), the main peak at 249 consistent


Page 20 of 45

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with the relative molecular mass of PPG which signifies that the one-armed product exists and only one aldehyde group in the PPA molecule reacted with GlyGly and the other is not. Further evidence of the formation of the benzoic imine bonds is provided by FTIR. As shown in Figure S4, the characteristic IR band of the imine at 1650 cm-1 is clearly visible in the spectrum of the PPG. Self-assembled behaviors The self-assembled behaviors of PPG were also different from those of OPGG. Unlike the gel self-assembly of OPGG, at the same situation, PPG was found self-assembling into vesicles at the reaction concentration (50 mM). To probe the morphology and diameter of the aggregates prepared from PPG, TEM, SEM and DLS were employed. As shown in Figure 5, vesicles with diameters of 200-300 nm are observed. DLS is used to further investigate the diameter of the vesicles (Figure 5b). The results show that the mean diameter is about 300 nm, which further verify the results from TEM and SEM.


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Figure 5. (a)

1H

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NMR spectra of PPA GlyGly and PPG. (b)

Dynamic size distribution of PPG vesicles (50 mM) in 90% methanol solution at pH 8.6. (c) TEM and (d) SEM images of PPG vesicles. Mechanism research Referring to the results above, we conjectured that the unique difference

between

OPA/GlyGly

and

the

products

PPA/GlyGly

and

systems

their

might

aggregates

ascribe

to

of the

different structures of OPA and PPA. Moreover, on account of the huge difference of the polarity between phthaldehyde and GlyGly,

intermediate

polarity

solvent


was

chosen,

which

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improved the self-assembly behaviors in the systems. In the reaction of forming dynamic imine bonds, the amino groups in GlyGly molecules and the aldehyde groups in OPA and PPA molecules were attractive to each other to form amine bonds under

alkaline

condition.

As

we

had

investigated,

the

dipeptide structures, GlyGly had strong polarity and sound foundations to form hydrogen bonds (O-H···N and N-H···O) with each other. For GlyGly, methanol solution is a poor solution, so GlyGly molecules tend to congregate with each other by hydrogen bonds.

For OPA molecules, the two aldehyde groups

were in ortho-position and close to each other. (Figure 6a) When one of the aldehyde groups reacted with a GlyGly molecule, the distance between the vicinal aldehyde group and GlyGly molecules was drawn closer and the polarity of the vicinal aldehyde group was increased, which facilitating the reaction of the vicinal aldehyde group and GlyGly molecules. The twoarmed product OPGG was preferentially generated. Furthermore, the hydrogen bonding interaction also existed between the two adjacent arms in OPGG, which improved the stability of the product and then promoted self-assembly of the product, which enhanced the thermodynamic stability of the product. However, for the PPA molecules, the aldehyde groups were in paraposition and far from each other. (Figure 6b) When one of the aldehyde group reacted with a GlyGly molecule, the opposite


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Page 24 of 45

aldehyde group was hard to react. The one-armed product PPG was

tend

to

generated.

Moreover,

the

polarity

and

hydrophilic/hydrophobic nature of the two ends of product were widely different with each other, causing the one-armed product to self-assemble into vesicles. In view of the strong polarity of the solvent, the ends of benzaldehyde groups with weaker

polarity

were

wrapped

inside

and

the

other

ends

connected with GlyGly molecules baring outside, which further preventing

the

amino

groups

in

GlyGly

molecules

from

approaching the aldehyde groups in PPA molecules. Furthermore, the self-assembly behavior also improved the thermodynamic stability of the one-armed product. Therefore, it was easy to understand that the reaction of PPA and GlyGly molecules only formed one-imine-bond product, PPG, and then self-assembled into vesicles, which different from the OPA/GlyGly system.


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Figure 6. Simulation of the reaction and self-assembly process of OPA/GlyGly PPA/GlyGly and MPA/GlyGly systems. pH-responsiveness The imine bonds in PPG were also confirmed reversible and the morphology of vesicles was controllable by pH. As probed by 1H

NMR in Figure S5, when pH is changed down to 6.4, the

chemical shift at 8.5 ppm corresponding to the imine bond disappears, accompanied by the enhancement of the signal at 10.0 ppm, which corresponds to the aldehyde proton. When the pH is changed back to 8.6, the imine signal recovers and aldehyde signal becomes weaker again. The 1H NMR results prove that the imine bonds in PPG can be dissociated by changing


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Page 26 of 45

down the pH to 6.4 and can be also recovered when the pH changed back again. In view of the reversible pH-responsiveness of imine bond shown above, as we speculated, the aggregates assembled by PPG can also be reversibly controlled by changing pH. As it has

been

investigated

that,

PPG

can

self-assemble

into

vesicles. (Figure 5) When the pH is decreased to 6.4, the vesicles disassemble and rupture. When the pH value is raised back to 8.6, the vesicles reform to the original vesicular size and vice versa (Figure S6).

MPA/GlyGly system When it came to MPA, the same reaction with GlyGly was also carried out at the same condition. Like OPA and PPA, the aldehyde groups in MPA molecules were also capable to combine with the amine groups of GlyGly molecules by benzoic imine bonds in alkaline condition. However, unlike OPA and PPA, the product of the reaction of MPA and GlyGly (with molar ratio 2:1, too) was not exclusive. There were two types of products appeared at the same time. One was the one-armed product (MPG) in which only one aldehyde group reacted, and the other was two-armed product (MPGG) in which both aldehyde groups in MPA


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molecules were all connected with GlyGly molecules by imine bonds. As probed by EMI-MS spectrometry (Figure S7), the two main peaks occurring in the EMI-MS spectrometry, 249 and 383, which corresponding to the relative molecular mass of MPG and MPGG.

1H

NMR spectroscopy (Figure S8) and FTIR (Figure S9)

were also employed to confirm the product obtained from the reaction of MPA and GlyGly. The results of the reaction were just as our conjecture. (Figure 6c) The two aldehyde groups in MPA molecule were in meta-position, and the distance between each other was not as close as the two aldehyde groups in OPA and also not as far away as those in PPA. Therefore, after one of the aldehyde group in MPA molecule reacted with a GlyGly molecule, the reaction probability of the other aldehyde group was lower than those in OPA but higher than MPA. Thus caused the products of MPA and GlyGly include both one-armed product MPG and two-armed product MPGG. Moreover, no aggregates like gels or vesicles self-assembled from the product were found, which might attribute to the mixture product, which had different molecular arrangements. Furthermore, the reaction results of MPA and GlyGly also certified our speculation about the reaction

mechanism

that

the

structure


isomerisms

of

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Page 28 of 45

phthalaldehydes had an effect on the reaction product and their self-assemblies. The adjacent aldehyde groups in benzene ring contribute to the more complete reaction with the amino groups in GlyGly by dynamic imine bond, on account of the hydrogen bonds between the dipeptide structure, GlyGly. The single product like OPGG and PPG had better chance to induce the formation of selfassembly

by

noncovalent

cycled force,

molecular which

arrangement

revealed

the

via

the

same

structure-property

relationship.

Special phenomenon In addition, while studying the reaction of OPA and GlyGly, an

interesting

phenomenon

was

found

by

accident.

When

moderate amount of OPA (50 mM) and GlyGly (100 mM) were mixed together in deionized water and without KOH involved, the mixture

solution

ultrasound,

a

became

dark

black

dark

rapidly.

suspension

Need

was

only

20

obtained,

min

which

different from the reaction of OPA and GlyGly in methanol solution with KOH. The product was acquired after washed and rotary evaporated. To explore the chemical structure of the product, EMI-MS

1H

NMR and FTIR were utilized. According to


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the

spectra

of

EMI-MS

1H

NMR

together with the literature

52,

and

FTIR

(Figure

S10-12),

the reaction of OPA and GlyGly

in aqueous can be confirmed as scheme 3.

Scheme 3. Reaction route of OPA and GlyGly in H2O without KOH. The product (OPG) was also found self-assembling in aqueous at reaction concentration (50 mM). Similar with the PPG molecules, the OPG molecules also had a conjugated structure to form π-π stacking with each other. Moreover, the OPG molecules is amphiphilic and tends to assemble into organic nanoparticles in aqueous solution, with the hydrophobic end wrapped

inside

hydrophilic solubility

to

part in

avoid exposed

water.

53

contacting outside TEM

and

with

to SEM

water

increase were

and

the

molecular

employed

to

investigate the morphology of the aggregates assembled from OPG in aqueous solution. As shown in Figure 7, OPG assembles into organic nanoparticles with an average diameter of 100200 nm in aqueous media. DLS is used to further investigate the diameter of the vesicles (Figure S13). The results show that the mean hydrodynamic diameter is about 200 nm, slightly


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Page 30 of 45

larger than the observation of TEM and SEM images due to the hydration.

Figure 7. (a) TEM and (b) SEM images of OPG aggregates (50 mM) in H2O.

Conclusion In conclusion, we dedicated to fabricating distinguishing reversible

and

controllable

pH-responsive

self-assembled

systems by using GlyGly and phthaldehydes (ortho, para and meta) based on the dynamic imine bonds. Owing to the different structure isomerisms, OPA, PPA and MPA generated different product and self-assemblies with GlyGly by dynamic imine bonds. Considering the dipeptide structures of GlyGly tended to form hydrogen bonds with each other, in the reaction of OPA and GlyGly, the two aldehyde groups in OPA molecules both readily combined with the GlyGly by benzoic imine bonds to


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Langmuir

form the two-armed product, OPGG. While, the OPGG was also prone to form hydrogen bonds between the two arms to improve the stability of product and the extent of reaction. The OPGG was able to self-assemble into a fine self-supporting gel by hydrogen bonds and π-π stacking. On account of the reversible pH-responsiveness of benzoic imine bonds, the gel also showed reversible

formation

controlled

by

pH.

When

it

came

to

PPA/GlyGly system, the two aldehyde groups of PPA were in para-position and far from each other. Only one of aldehyde groups reacted with GlyGly to form the one-armed product with only an imine bonds, PPG, which was found self-assembling into vesicles due to the π-π stacking of benzene ring in the reaction condition (50 mM) in 90% methanol solution at pH 8.6, resulting the aldehyde group wrapped inside and the other end which connected with GlyGly exposed outside to improve the solubility in solution. The supramolecular self-assembled effect can also prevent the unreacted aldehyde group from contacting with the GlyGly. Therefore, in the reaction of PPA and GlyGly, one-armed product was easier to generate. Similar with the gel assembled from OPGG, the vesicles assembled from PPG were also reversible pH-responsiveness controlled by pH via dynamic amine bonds. While for MPA/GlyGly system, the one-armed product MPG and two-armed product MPGG were both detected. Due to the product was not single, no aggregates


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Page 32 of 45

were observed in the methanol solution at pH 8.6. Moreover, a

different

type

of

reaction

leading

to

a

benzopyrrole

structure was found via OPA and GlyGly mixed together in aqueous solution. Furthermore, influenced by the structure isomerisms, covalent

the

bonds

unique reaction

different and

behaviors

reversible

of

dynamic

pH-responsiveness

self-assemblies among OPA/GlyGly, PPA/GlyGly and MPA/GlyGly systems might provide a new path to realize specific selective reaction

products

possessing chemical

and

reversible

bonds,

which

then

to

design

responsiveness maybe

widely

diverse based

used

for

assemblies on

dynamic

intelligent

materials.

ASSOCIATED CONTENT Supporting Information ESI-MS spectrum of OPGG, PPG, OPG and the product of reaction MPA and GlyGly, FTIR spectroscopy information, 1H NMR, TEM and SEM of PPA/GlyGly system, 1H NMR spectra of MPA GlyGly and their product and the product of OPA and GlyGly reaction, DLS are included in the supporting information. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION


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Corresponding Author * E-mail: [email protected]

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT We thank Zihan Zhang, Xiang Liu, Huilan Hu, and Shuangzhan Lou from Shandong University for their assistance during their innovative experiments project. REFERENCES

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